This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the United States, asthma affects 14.6 million people and accounts for economic losses of more than $14 billion a year. Adolescents are the fastest growing asthma demographic, suggesting that the effects of this disease will be felt well into the future. Vasoactive intestinal peptide (VIP) is a critical protein in the initiation and maintenance of allergic airway disease. When acting through its G protein-coupled receptor, VPAC2, it supports a Th2 phenotype, which promotes asthma. It is a neuropeptide with cytokine functionality that is degraded quickly in the na[unreadable]ve lung by neutral endopeptidase produced by the epithelium. When the epithelium is lost during sloughing that occurs in asthma, the peptidase is also lost. As a result of decreased degradation, the actions of VIP are enhanced. We believe that VIP functions to protect the integrity of the damaged pulmonary interface by initiating a fibrotic barrier through the downregulation of matrix metalloproteinase (MMP)-2, which is normally responsible for wound healing and eosinophil efflux into the airway lumen. The proposed experiments are focused to determine the mechanisms by which MMP-2 is regulated and the role of MMP-2 in asthma. The management of this regulation may provide new clinical strategies to treat established airway disease that historically has been difficult to address.